Published on Web 08/05/2003
Scandium-Catalyzed Allylboration of Aldehydes as a Practical Method for Highly Diastereo- and Enantioselective Construction of Homoallylic Alcohols Hugo Lachance, Xiaosong Lu, Michel Gravel, and Dennis G. Hall* Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada Received June 20, 2003; E-mail:
[email protected] Carbonyl allylation chemistry is one of the most useful tools in modern organic synthesis.1 Despite extensive investigations, there is yet no general method using simple and stable allylation reagents for the stereocontrolled formation of a wide variety of homoallylic alcohol products (eq 1). Of particular significance is the challenging
problem of controlling both diastereo- and enantioselectivity in aldehyde crotylation, a process allowing the elaboration of syn and anti propionate units ubiquitous in several classes of natural products (eq 1, R1,R2 ) H,CH3 or CH3,H). Reagents of boron, silicon, and tin have emerged as the most popular crotyl transfer agents for achiral aldehydes.1 The most stereoselective methods,2-9 however, suffer from one or many drawbacks such as air or moisture sensitivity, the need for a multistep preparation of chiral reagents, or incompatibility with aliphatic aldehydes. Thus, the search continues for an efficient, practical solution to the problem of stereoselective aldehyde crotylation and allylations in general. We10 and others11 have recently reported the first examples of metal-catalyzed additions of allylboronates. Further to the remarkable rate enhancement, there are significant implications to the fact that this novel catalytic manifold preserves the diastereospecificity of uncatalyzed allylborations. These findings pave the way to the development of more effective methods to access aldol-like adducts with high enantiocontrol. Herein, we describe a general approach for the allylation of aldehydes using stable, air-tolerant chiral allylboronates under Sc(OTf)3 catalysis. This practical methodology provides both syn and anti propionate units and other homoallylic alcohols with very high diastereo- and enantioselectivity for several substrates, including functionalized aliphatic aldehydes useful toward the elaboration of complex natural products. There are no chiral allylboronic esters known to afford practical levels of enantioselectivity (>95% ee) in additions to achiral aldehydes under typical low-temperature conditions (-78 °C).1 On the basis of the potential beneficial effect of a lower reaction temperature and the different mechanistic nature of the metalcatalyzed manifold on the enantioselectivity, we planned to revisit a number of known chiral diol auxiliairies for boronic acids. At the outset, the allylation of benzaldehyde was investigated using different solvents, temperatures, and Lewis acids identified from our previous studies.10 A small set of allylboronates 1 derived from chiral diol precursors a-e was compared under these variables (Figure 1). Using allylboronate (-)-1a, these investigations revealed that Sc(OTf)3 is significantly more active than other Lewis acids and provided the highest enantiomeric excess in the formation of homoallylic alcohol 5 (Table 1, entries 1-7). A pronounced solvent effect was observed, with dichloromethane standing out as the most 10160
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Figure 1. Chiral allylboronates evaluated for enantioselective Lewis acidcatalyzed additions onto aldehydes. Table 1. Lewis Acid-Catalyzed Allylboration of Benzaldehydea
entry
boronate
L. A.b
solvent c
temp (°C)
time (h)
conv.d (%)
ee e (%)
1 2 3 4 5 6 7 8 9 10 11 12 13
1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d 1e
none AlCl3 TiCl4 TfOH Cu(OTf)2 Yb(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene hexanes CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
25 -78 -78 -78 -40f -40f -78 -78 -78 -78 -78 -78 0
72 2 2 2 2 2 2 2 2 2 2 2 2
50 14 22 72 4 4 90 30 20 62 100 100 0
11 63 78 84 52 38 92 46 8 84g 9 7 -
a Reaction scale: approximately 0.4 mmol (>100 mg) of (-)-1 (1.1 equiv), and PhCHO (1 equiv). b Lewis acid, 10 mol %. c Typically 0.5 M concentration in allylboronate. d Measured by integration of representative signals by 1H NMR on crude product obtained after an appropriate workup. e Measured by chiral HPLC (see Supporting Information for details). f No reaction observed at -78 °C. g Opposite enantiomer is predominant.
efficient one both in terms of conversion and ee (entries 7-9). Whereas pinanediol-derived 1c and the tartrate-based reagents 1d12 and 1e13 gave disappointing results (entries 11-13), the Hoffmann camphor-based allylboronates 1a and 1b14 gave high enantioselectivities under Sc(OTf)3 catalysis (entries 7, 10). Further optimization confirmed that molecular sieves are not required and that the preferred order of addition involves mixing the aldehyde with Sc(OTf)3 in CH2Cl2 at -78 °C, followed by the allylboronate. Developed more than two decades ago, the Hoffmann camphorbased allylboronates were the first chiral allylboron reagents ever reported.14 The advantages of the new, low-temperature catalytic manifold are remarkable. In the absence of a catalyst (e.g., entry 1), 1a and 1b are unreactive at -78 °C and afford modest ee’s (98%). Compared to 1a and 2a, additions of crotylboronates 3a (E) and 4a (Z) are slower and usually required the use of an excess of one substrate to provide acceptable yields.15 Reactions of R-branched aliphatic aldehydes provided only low yields of products.15 Despite these current limitations, it is particularly significant that functionalized aliphatic aldehydes such as TBDPSOCH2CH2CHO and TBDMSOCH2CHO effectively provide addition products with great
utility as early intermediates in the synthesis of complex natural products. To demonstrate the potential of this methodology in practical-scale preparation, the reaction of entry 9 was carried out with a gram quantity of 2a. Using only 5 mol % of Sc(OTf)3, alcohol 13 was obtained in a satisfying 71% yield and 96% ee. To the best of our knowledge, this method represents the most effective system for enantioselective methallyl transfer onto aldehydes,16 which suggests that a new generation of highly enantioselective β-substituted allylating agents could be developed. At this time, the precise mechanistic nature of this Lewis acidcatalyzed process and the mode of stereoinduction are unknown. On the basis of preliminary arguments presented earlier10 and the fact that the diastereospecificity of the noncatalyzed reaction is preserved, the allylboration is thought to proceed via the usual cyclic transition state, with electrophilic boron activation by metal coordination to the boronate oxygens. In conclusion, we have reported a remarkably general and practical aldehyde allylation methodology based on the Sc(OTf)3catalyzed reaction of stable chiral allylboronates. This approach is unrivaled in many ways, in particular, its efficient control of both diastereo- and enantioselectivity. We anticipate that this new metalcatalyzed allylboration process will find use in the synthesis of complex natural products, thereby giving new life to the camphorbased allylboronates. Acknowledgment. This work was funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada and the University of Alberta. H.L. thanks the Alberta Ingenuity Fund, and M.G. thanks NSERC and the Alberta Heritage Foundation for Medical Research (AHFMR) for graduate scholarships. The authors thank Dr. Jason Kennedy for helpful advice and discussions. Supporting Information Available: Full experimental details, characterization data, and spectral reproduction for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org. References (1) For reviews, see: (a) Denmark, S. E.; Almstead, N. G. Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10, pp 299-402. (b) Chemler, S. R.; Roush, W. R. Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 11, pp 403-490. (2) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923. (3) Garcia, J.; Kim, B.; Masamune, S. J. Org. Chem. 1987, 52, 4831-4832. (4) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 54955496. (5) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339-6348. (6) Marshall, J. A. Chem. ReV. 1996, 96, 31-47. (7) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (8) (a) Aldersen, M.; Hildebrandt, B.; Koster, G.; Hoffmann, R. W. Chem. Ber. 1989, 122, 1777-1782. (b) Hoffmann, R. W.; Dresely, S. Angew. Chem., Int. Ed. Engl. 1986, 25, 189-190. (9) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488-9489. (10) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 1158611587. (11) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 12414-12415. (12) Roush, W. R.; Walts, A. G.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186-8190. (13) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 2000, 65, 9194-9200. (14) Herold, T.; Schrott, U.; Hoffmann, R. W. Chem. Ber. 1981, 111, 359374. (15) Efforts to improve conversions with 3a and 4a, and reactions of branched aldehydes, are currently being pursued and will be reported in due course. (16) Other methods afford lower enantioselectivities or are less general. For example, see ref 4 and: (a) Brown, H. C.; Jadhav, P. K.; Perumal, P. T. Tetrahedron Lett. 1984, 25, 5111-5114. (b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827-7830.
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